In the absence of a vaccine, there is an urgent need for an effective topical microbicide for the prevention of HIV transmission worldwide. Because of the speed at which the epidemic has spread, it is crucial for the global community to expand female-controlled preventive options such as the use of microbicides. Our long-term goal is to develop effective strategies that can restrict or prevent HIV transmission. Our Indian collaborators have developed a polyherbal vaginal microbicide named "BASANT" that inhibits a wide range of sexually transmitted pathogens including HIV. The preliminary studies have also shown safety and acceptability in Phase I and Phase II human trials in India. Therefore, our objective in this application is to verify the effectiveness of the Basant in preventing HIV transmission in vivo. Our central goal of these studies is to determine the efficacy of a Basant in preventing intravaginal/intrarectal HIV transmission in humanized mouse model (Specific objective 1) and to understand the mechanism of microbicide anti-HIV action (Specific objective 2) and in the process may enable for the development of most effective anti-HIV-1 intravaginal/intrarectal microbicide. In addition, the efficacy of Basant will be evaluated against six major globally prevalent strains of genetically and biologically characterized HIV-1 isolates that may help to prevent HIV transmission in different developing/developed countries of the World. Finally, we will conduct in vitro experiments to characterize the escape pathways used by HIV-1 under the selection pressure of an inhibitor, Basant. Basant will be used to generate candidate escape mutants against a broad range of R5 HIV-1 isolates from different genetic subtypes. The proposed research is highly innovative and significant, because the new knowledge gained from this study may lead to the development of novel antiviral microbicides with public health significance. The use of vaginal microbicide that reduce the risk per exposure is likely to exert a tremendous effect on the reduction of HIV transmission. The proposed research is highly innovative and significant, because the new knowledge gained from this study may lead to the development of novel antiviral microbicides with public health significance. The use of vaginal microbicide that reduce the risk per exposure is likely to exert a tremendous effect on the reduction of HIV transmission on a global basis.